Transmucosal ketamine delivery composition

ABSTRACT

Disclosed are preparations and formulations of high thermodynamic activity lipophilic associations (LA), in which there is pairing between an ionizable pharmaceutical agent and a lipophilic species having ionic characteristics opposite to that of the pharmaceutical agent. Such lipophilic associations manifest high thermodynamic activity, as evidenced by their being predominantly in a liquid phase at room temperature or solvated in a lower-than-water dielectric solvent. Further the pharmaceutical agent being solubilized means that dissolution is not rate limiting to transmucosal absorption. This LA or LA-solvate is formulated into a low dielectric dosage form, from when, upon the dosage form&#39;s hydration, the pharmaceutical agent is driven through the mucosal tissue and into systemic circulation. The invention therefore provides an enhanced transmucosal drug delivery system for ionizable pharmaceutical agents at or near physiological pH.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 14/211,317,filed on Mar. 14, 2014, which is a continuation-in-part of U.S. Ser. No.10/545,774, filed on Aug. 8, 2006, now U.S. Pat. No. 8,992,974, whichissued on Mar. 31, 2015, which is a National Stage application under 35U.S.C. §371 and claims benefit under 35 U.S.C. §119(a) of InternationalApplication No. PCT/US2004/005490, having an International Filing Dateof Feb. 24, 2004, which claims benefit of U.S. Provisional ApplicationSer. No. 60/449,647 filed on Feb. 24, 2003, the contents of each ofwhich are incorporated herein by reference in their entireties. Thisapplication is also related to U.S. Ser. No. 14/634,693, filed on Feb.27, 2015.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition thatcontains an ionizable pharmaceutical agent and a one or morecomplementary lipophilic species where the ionizable pharmaceuticalagent and the one or more complementary lipophilic species areformulated in a transmucosal dosage form. In certain embodiments of theinvention, the ionizable pharmaceutical agent is hydrogen-bonded to thecomplementary lipophilic species, or is ion-paired to the complementarylipophilic species, to form a lipophilic association (LA). Thepharmaceutical composition may further contain a solvent having adielectric constant less than that of water, wherein the LA is solvatedin the solvent to form a solubilized LA. Examples of solvents includeethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,tributyl citrate, a polyethylene glycol, propylene glycol, bisabolol,glycerin, mineral oil, ethyl oleate, fatty acid esters, squalane, animaloils, vegetable oils, hydrogenated vegetable oils, isopropyl myristate,isopropyl palmitate, glycofurol, terpenes, essential oils, alcohols,polyols, or silicone fluids. The pharmaceutical composition of thepresent invention may further contain a carrier, wherein the LA, orsolubilized LA, is adsorbed or absorbed to the carrier. The carrier maybe, for example a silica or a silicified microcrystalline cellulose. Thepharmaceutical composition of the present invention may further containa water-soluble excipient. Such an excipient may possess a dielectricconstant less than the dielectric constant of water. Examples ofwater-soluble excipients useful in the present invention include sugar,polyol, alcohol, saccharide, polysaccharide, glycerin, propylene glycol,ethanol, isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate,tributyl citrate, a dextrate, dextrin, dextrose, fructose, lactitol,lactose, erythritol, maltose, maltitol, maltodextrin, polydextrose,trehalose, mannitol polyethylene glycol, sorbitol, sucrose or xylitol.

In the present invention, the molar ratio of lipophilic species toionizable pharmaceutical agent is at least about 1:1. In one embodiment,the pharmaceutical agent possesses a basic functional group and thelipophilic species is an acid. In the present invention, the lipophilicspecies is a fatty acid, a long-chain alkyl sulfonic acid, or along-chain alkyl sulfuric acid. Examples of long-chain alkyls that arefound in the fatty acid, sulfonic acid or sulfuric acid are caproic,caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,ricinoleic, linoleic, linolenic, licanic, arachidonic and/orclupanadonic acid.

In an alternative, the pharmaceutical agent possesses an acidicfunctional group and the lipophilic species is a base. In certainembodiments, the lipophilic species is a amine or amide, such ascetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammoniumchloride, a quaternary surfactant, cetylpyridinium chloride, hexetidine,benzalkonium chloride or an amine or amide of caproic, caprylic, capric,lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric,myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic,linolenic, licanic, arachidonic or clupanadonic acid.

In certain embodiments of the present invention the carrier is capableof forming an inclusion complex with the LA or solubilized LA. Thepharmaceutical composition of the present invention may further containa carrier, wherein the LA, or solubilized LA, is adsorbed or absorbed tothe carrier. The carrier may be, for example a silica or a silicifiedmicrocrystalline cellulose.

Examples of pharmaceutical agents that may be used in embodiments of thepresent invention include one or more of the following: aantihypertensive agent, analgesic, antidepressant, opioid agonist,anesthetic, antiarrhythmic, antiarthritic, antispasmodic, ACE inhibitor,decongestant, antibiotic, antihistamine, anti-anginal, diuretic,anti-hypotensive agent, anti-Parkinson agent, bronchodilator, oxytocicagent, anti-diuretic, anti-hyperglycemic, antineoplastic and/orimmunosuppresent agent, antiemetic, anti-infective, antifungal,antiviral, antimuscarinic, antidiabetic agent, antiallergy agent,anxiolytic, sedative, antipsychotic, bone modulating agent,cardiovascular agent, cholesterol lowering drug, antimalarial,antiepileptic, antihelminthic, agent for smoking cessation, coughsuppressant, expectorant, mucolytic, nasal decongestant, dopaminergic,gastrointestinal agent, muscle relaxant, neuromuscular blocker,parasympathomimetic, prostaglandin, stimulant, anorectic, thyroid orantithyroid agent, hormone, antimigrane agent, antiobesity, and/ornon-steroidal anti-inflammatory agent. Further, the pharmaceutical agentmay be one or more of the following: dihydroergotamine, fentanyl,sufentanil, lidocaine, alfentanil, lofentanil, carfentanil,pentobarbital, buspirone, ergotamine, bisphosphonate, alendronic acid,nalbuphine, bupropion, metformin, diethylcarbamazine, tramadol, heparinor a heparin derivative, amoxicillin, gabapentin, econazole, aspirin,prostaglandin, methylsergide, ergonovine, endorphins, enkephalins,oxytocin, opiates, heparin and its derivatives, clorazepic acid,barbiturate, albuterol, atropine, scopolamine, selegiline, timolol,nicotine, cocaine, novocaine, amphetamines, caffeine, methylphenidate,chlorpromazine, ketamine, the R and/or S enantiomers of ketamine,ketamine active metabolites norketaminek, dehydronorketamine,epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol,metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan,bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine, ortetracaine. In one example, the pharmaceutical agent is nicotine.

In certain embodiments of the present invention, the pharmaceuticalcomposition further contains a buffering agent, colorant, flavoring,solvent, co-solvent, coating agent, binder, diluent, carrier,disintegrant, glident, lubricant, opacifying agent, humectant,granulating agent, gelling agent, polishing agent, suspending agent,sweetening agent, anti-adherent, preservative, emulsifying agent,antioxidant, levigating agent, plasticizer, surfactant, tonicity agent,viscosity agent, enteric agent, enteric coating, controlled-releaseagent or coating, wax, wetting agent, thickening agent, suppositorybase, stiffing agent, stabilizing agent, solubilizing agent,sequestering agent, ointment base, oleaginous vehicle, film-formingagent, essential oil, emollient, dissolution enhancer, dispersing agent,or cryoprotectant or combination thereof. Examples of buffering agentsinclude phosphates, carbonates, tartrates, borates, citrates, acetates,and maleates.

In the present invention, the composition may be prepared as a buccaltablet, sublingual tablet, oral capsule, oral tablet, nasal spray,buccal or vaginal spray, liquid/semisolid, aerosol for nasal, buccal orpulmonary delivery, patch, lozenge, gum, lollypop, film, strip, paper,suppository, or pessary dosage form.

In the present invention, when the pharmaceutical composition isdissolved in water, has a pH of about physiological pH of a targetmucosal membrane.

The present invention further provides a method for transmucosaldelivery of an ionizable pharmaceutical agent The method includes thefollowing steps: admixing an ionizable pharmaceutical agent with a oneor more complementary lipophilic species to form a lipophilicassociation (LA); formulating the LA in a transmucosal dosage form; andadministering the transmucosal dosage form to a targeted mucosalmembrane in order to deliver the pharmaceutical agent through themucosal membrane and into systemic circulation. The admixing step of thepresent invention is performed under conditions such that the ionizablepharmaceutical agent hydrogen-bonds with the complementary lipophilicspecies, or ionizable pharmaceutical agent ion-pairs with thecomplementary lipophilic species. The method of the present inventionmay also include the step of solubilizing the LA with a solvent having adielectric constant less than that of water to form a solubilized LA.Examples of solvents that may be used in the present method includeethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,tributyl citrate, polyethylene glycol, propylene glycol, bisabolol,glycerin, mineral oil, ethyl oleate, fatty acid esters, squalane, animaloil, vegetable oil, hydrogenated vegetable oil, isopropyl myristate,isopropyl palmitate, glycofurol, terpene, essential oil, alcohol,polyol, and/or a silicone fluid.

The transmucosal dosage form may further include a carrier, wherein theLA, or solubilized LA, is adsorbed or absorbed to the carrier. Examplesof carriers include silica or silicified microcrystalline cellulose. Thetransmucosal dosage form may further include a water-soluble excipient.The excipient may possess a dielectric constant less than the dielectricconstant of water. Examples of suitable water-soluble excipients aresugars, polyols, alcohols, saccharides, polysaccharides, glycerin,propylene glycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin,triethyl citrate, tributyl citrate, dextrates, dextrins, dextrose,fructose, lactitol, lactose, erythritol, maltose, maltitol,maltodextrins, polydextroses, trehalose, mannitol, polyethylene glycols,sorbitol, sucrose and/or xylitol.

In the present invention, the molar ratio of lipophilic species toionizable pharmaceutical agent is at least about 1:1. In one embodiment,the pharmaceutical agent possesses a basic functional group and thelipophilic species is an acid. In the present invention, the lipophilicspecies is a fatty acid, a long-chain alkyl sulfonic acid, or along-chain alkyl sulfuric acid. Examples of long-chain alkyls that arefound in the fatty acid, sulfonic acid or sulfuric acid are caproic,caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,ricinoleic, linoleic, linolenic, licanic, arachidonic and/orclupanadonic acid.

In an alternative, the pharmaceutical agent possesses an acidicfunctional group and the lipophilic species is a base. In certainembodiments, the lipophilic species is a amine or amide, such ascetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammoniumchloride, a quaternary surfactant, cetylpyridinium chloride, hexetidine,benzalkonium chloride or an amine or amide of caproic, caprylic, capric,lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric,myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic,linolenic, licanic, arachidonic or clupanadonic acid.

In certain embodiments of the present invention the carrier is capableof forming an inclusion complex with the LA or solubilized LA. Thepharmaceutical composition of the present invention may further containa carrier, wherein the LA, or solubilized LA, is adsorbed or absorbed tothe carrier. The carrier may be, for example a silica or a silicifiedmicrocrystalline cellulose.

In certain embodiments of the present invention, the pharmaceuticalagent may be one or more of the following: a antihypertensive agent,analgesic, antidepressant, opioid agonist, anesthetic, antiarrhythmic,antiarthritic, antispasmodic, ACE inhibitor, decongestant, antibiotic,antihistamine, anti-anginal, diuretic, anti-hypotensive agents,anti-Parkinson agent, bronchodilator, oxytocic agent, anti-diuretic,anti-hyperglycemic, antineoplastic and/or immunosuppresent agent,antiemetic, anti-infective, antifungal, antiviral, antimuscarinic,antidiabetic agent, antiallergy agent, anxiolytic, sedative,antipsychotic, bone modulating agent, cardiovascular agent, cholesterollowering drug, antimalarial, antiepileptic, antihelminthic, agent forsmoking cessation, cough suppressant, expectorant, mucolytic, nasaldecongestant, dopaminergic, gastrointestinal agent, muscle relaxant,neuromuscular blocker, parasympathomimetic, prostaglandin, stimulant,anorectic, thyroid or antithyroid agent, hormone, antimigrane agent,antiobesity, and/or non-steroidal anti-inflammatory agent. Further, thepharmaceutical agent may be one or more of the following:dihydroergotamine, fentanyl, sufentanil, lidocaine, alfentanil,lofentanil, carfentanil, pentobarbital, buspirone, ergotamine,bisphosphonate, alendronic acid, nalbuphine, bupropion, metformin,diethylcarbamazine, tramadol, heparin or a heparin derivative,amoxicillin, gabapentin, econazole, aspirin, prostaglandin,methylsergide, ergonovine, endorphins, enkephalins, oxytocin, opiates,barbiturate, albuterol, atropine, scopolamine, selegiline, timolol,nicotine, cocaine, novocaine, amphetamines, caffeine, heparin and itsderivatives, clorazepic acid, methylphenidate, chlorpromazine, ketamine,epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol,metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan,bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine, ortetracaine. In one embodiment the pharmaceutical agent is ketamine. Insome embodiments, the ketamine is the R enantiomer, the S enantiomer, ora mixture of both.

In embodiments of the present invention, the transmucosal dosage formmay additionally contain a buffering agent, colorant, flavoring,solvent, co-solvent, coating agent, binder, diluent, carrier,disintegrant, glident, lubricant, opacifying agent, humectant,granulating agent, gelling agent, polishing agent, suspending agent,sweetening agent, anti-adherent, preservative, emulsifying agent,antioxidant, levigating agent, plasticizer, surfactant, tonicity agent,viscosity agent, enteric agent, enteric coating, controlled-releaseagent or coating, wax, wetting agent, thickening agent, suppositorybase, stiffing agent, stabilizing agent, solubilizing agent,sequestering agent, ointment base, oleaginous vehicle, film-formingagent, essential oil, emollient, dissolution enhancer, dispersing agent,or cryoprotectant or combination thereof.

In the method of the present invention, the buffering agent may be aphosphate, carbonate, tartrate, borate, citrate, acetate, and/ormaleate.

The target mucosal tissue may be oral mucosa, esophagus,gastrointestinal tract, lungs, rectum, sinuses, eye, urinary tract or alining of a female reproductive organ. In the method of the presentinvention, the ionizable pharmaceutical agent is delivered rapidlyacross the mucosal membrane. For example, the ionizable pharmaceuticalagent is delivered across the mucosal membrane in about 10 minutes orless.

In the present invention, the pharmaceutical composition when dissolvedin water has a pH near the physiological pH of the target mucosalmembrane.

The present invention also provides a method of manufacturing atransmucosal pharmaceutical unit dosage forms described above. Themanufacturing method involves the following steps: admixing an ionizablepharmaceutical agent with a one or more complementary lipophilic speciesto form a lipophilic association (LA); and formulating the LA into atransmucosal unit dosage form. The admixing is performed underconditions such that the ionizable pharmaceutical agent hydrogen-bonds,or ion-pairs, with the complementary lipophilic species. The method mayfurther involve admixing an adsorbent, a water-soluble excipient, adisintegrant and a lubricant. In one example, the water solubleexcipient is mannitol, the disintegrant is sodium starch glycolate andthe lubricant is sodium stearyl fumarate.

In certain embodiments, the LA is formed into a buccal tablet,sublingual tablet, oral capsule, oral tablet, nasal spray, buccal orvaginal spray, liquid/semisolid, aerosol for nasal, buccal or pulmonarydelivery, patch, lozenge, gum, lollypop, film, strip, paper,suppository, or pessary dosage form. The dosage forms may bemanufactured by direct tablet compression, wet or dry granulation, drypowder blends, molding, spray-congealing, powder layering, tableting,encapsulating, spray-drying, spheronization, triturates, lyophilization,freeze drying, co-melt, microencapsulation, troching, pelleting,aerosolizing, liquid or semisolid processes manufacturing.

The present manufacturing method may further involve solubilizing the LAwith a solvent having a dielectric constant less than that of water toform a solubilized LA. Examples of solvents include one or more of thefollowing: ethanol, ethyl acetate, isopropyl alcohol, triacetin,triethyl citrate, tributyl citrate, polyethylene glycols, propyleneglycol, bisabolol, glycerin, mineral oil, ethyl oleate, fatty acidesters, squalane, animal oils, vegetable oils, hydrogenated vegetableoils, isopropyl myristate, isopropyl palmitate, glycofurol, terpenes,essential oils, alcohols, polyols, and/or silicone fluids.

The present manufacturing method may further involve admixing a carrierwith the LA (or solubilized LA), wherein the LA (or solubilized LA) isadsorbed or absorbed to the carrier. Examples of carriers include asilica or a silicified microcrystalline cellulose. In the presentinvention, the transmucosal dosage form may further contain awater-soluble excipient. Such a water-soluble excipient may possess adielectric constant less than the dielectric constant of water. Examplesof water-soluble excipients include a sugar, a polyol, an alcohol asaccharide, a polysaccharide, glycerin, propylene glycol, ethanol,isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate, tributylcitrate, a dextrate, a dextrin, dextrose, fructose, lactitol, lactose,erythritol, maltose, maltitol, a maltodextrin, a polydextrose,trehalose, mannitol, a polyethylene glycol, sorbitol, sucrose and/orxylitol. In the present invention, the molar ratio of lipophilic speciesto ionizable pharmaceutical agent is at least about 1:1. In oneembodiment, the pharmaceutical agent possesses a basic functional groupand the lipophilic species is an acid. In the present invention, thelipophilic species is a fatty acid, a long-chain alkyl sulfonic acid, ora long-chain alkyl sulfuric acid. Examples of long-chain alkyls that arefound in the fatty acid, sulfonic acid or sulfuric acid are caproic,caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,ricinoleic, linoleic, linolenic, licanic, arachidonic and/orclupanadonic acid.

In certain embodiments of the present method, the pharmaceutical agentpossesses an acidic functional group and the lipophilic species is abase. In certain embodiments, the lipophilic species is a amine oramide, such as cetrimide, oleamidopropyl dimethylamine, didecyldimethylammonium chloride, a quaternary surfactant, cetylpyridinium chloride,hexetidine, benzalkonium chloride or an amine or amide of caproic,caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,ricinoleic, linoleic, linolenic, licanic, arachidonic and/orclupanadonic acid.

In the present method, the carrier is capable of forming an inclusioncomplex with the LA or solubilized LA. The pharmaceutical composition ofthe present invention may further contain a carrier, wherein the LA, orsolubilized LA, is adsorbed or absorbed to the carrier. The carrier maybe, for example a silica or a silicified microcrystalline cellulose.

Examples of pharmaceutical agents that may be used in the present methodinclude one or more of the following: a antihypertensive agent,analgesic, antidepressant, opioid agonist, anesthetic, antiarrhythmic,antiarthritic, antispasmodic, ACE inhibitor, decongestant, antibiotic,antihistamine, anti-anginal, diuretic, anti-hypotensive agents,anti-Parkinson agent, bronchodilator, oxytocic agent, anti-diuretic,anti-hyperglycemic, antineoplastic and/or immunosuppresent agent,antiemetic, anti-infective, antifungal, antiviral, antimuscarinic,antidiabetic agent, antiallergy agent, anxiolytic, sedative,antipsychotic, bone modulating agent, cardiovascular agent, cholesterollowering drug, antimalarial, antiepileptic, antihelminthic, agent forsmoking cessation, cough suppressant, expectorant, mucolytic, nasaldecongestant, dopaminergic, gastrointestinal agent, muscle relaxant,neuromuscular blocker, parasympathomimetic, prostaglandin, stimulant,anorectic, thyroid or antithyroid agent, hormone, antimigrane agent,antiobesity, and/or non-steroidal anti-inflammatory agent. Furtherexamples of pharmaceutical agents that may be used in the present methodinclude one or more of the following: dihydroergotamine, fentanyl,sufentanil, lidocaine, alfentanil, lofentanil, carfentanil,pentobarbital, buspirone, ergotamine, bisphosphonate, alendronic acid,nalbuphine, bupropion, metformin, diethylcarbamazine, tramadol, heparinor a heparin derivative, amoxicillin, gabapentin, econazole, aspirin,prostaglandin, methylsergide, ergonovine, endorphins, enkephalins,oxytocin, opiates, barbiturate, albuterol, atropine, scopolamine,selegiline, timolol, nicotine, cocaine, novocaine, amphetamines,caffeine, heparin and its derivatives, clorazepic acid, methylphenidate,chlorpromazine, ketamine, epinephrine, estropipate, naloxone,naltrexone, furosemide, labetalol, metoprolol, nadolol, isoproterenol,terbutaline, sumatriptan, bupivacaine, prilocalne, loratadine,chloropheniramine, clonidine, or tetracaine. In one embodiment, thepharmaceutical agent is nicotine.

In certain embodiments of the present method, the process involvesadmixing with the LA or solubilized LA a buffering agent, colorant,flavoring, solvent, co-solvent, coating agent, binder, diluent, carrier,disintegrant, glident, lubricant, opacifying agent, humectant,granulating agent, gelling agent, polishing agent, suspending agent,sweetening agent, anti-adherent, preservative, emulsifying agent,antioxidant, levigating agent, plasticizer, surfactant, tonicity agent,viscosity agent, enteric agent, enteric coating, controlled-releaseagent or coating, wax, wetting agent, thickening agent, suppositorybase, stiffing agent, stabilizing agent, solubilizing agent,sequestering agent, ointment base, oleaginous vehicle, film-formingagent, essential oil, emollient, dissolution enhancer, dispersing agent,or cryoprotectant or mixture thereof.

In certain embodiments of the present invention, the buffering agent isa phosphate, carbonate, tartrate, borate, citrate, acetate, and/ormaleate.

In certain embodiments of the present invention, the pharmaceuticalcomposition, when solubilzed in water, has a pH of about physiologicalpH of a target mucosal membrane.

Further, the present invention provides pharmaceutical products preparedby the methods of manufacture described above.

The present invention also provides a method of treating a patient inneed thereof by administering a pharmaceutical composition containing anionizable pharmaceutical agent and a one or more complementarylipophilic species, wherein the ionizable pharmaceutical agent and theone or more complementary lipophilic species are formulated in atransmucosal dosage form, and wherein the pharmaceutical composition isadministered as a bolus release across a mucosal membrane. In anembodiment of this method, the ionizable pharmaceutical agent isdelivered rapidly across the mucosal membrane, such as in about 10minutes or less. In some embodiments, the ionizable pharmaceutical agentis ketamine, its R and/or S enantiomers, and/or its active metabolites,norketamine and/or dehydronorketamine. In one embodiment, thepharmaceutical composition is has a pH of about physiological pH of atarget mucosal membrane. For example, in one embodiment nicotine istransmucosally delivered sublingually at a pH between about 5.5 andabout 7.5.

In some embodiments, the present disclosure provides a method fortreating depression, suicidal ideation, pain, anesthesia, analgesia posttraumatic shock disorder, and other central nervous systems diseasestates for which ketamine is an effective therapeutic, in a patient inneed thereof, comprising: administering the pharmaceutical compositionof according to the disclosure to the buccal or sublingual cavity of thepatient, whereby a therapeutically effective amount of ketamine isreleased and is systemically administered to the patient within 5minutes to 15 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing a method of manufacture of a nicotinesublingual/buccal tablet according to the invention.

FIG. 2 is a graph showing a dissolution profile of nicotine as deliveredby a formulation according to the invention and compared to adissolution profile of prior-art formulations.

FIG. 3 is a schematic showing a method of manufacture of an epinephrinesublingual/buccal tablet according to the invention.

FIG. 4 is a schematic showing a method of manufacture of a fentanylsublingual/buccal tablet according to the invention.

FIG. 5 is a schematic showing a method of manufacture of alendronic acidsublingual/buccal tablet according to the invention.

FIG. 6 is a schematic showing a method of manufacture of a clorazepicacid sublingual/buccal tablet according to the invention.

FIG. 7 is a graph showing a dissolution profile of nicotine as deliveredby a formulation according to the invention and compared to adissolution profile of prior-art formulations.

FIG. 8 is a graph of a sublingual nicotine formulation mucosalpermeation rate compared to a prior art formulation.

FIG. 9 is a graph of a sublingual nicotine formulation plasma level overtime compared to prior art formulations.

FIG. 10 is a graph comparing vital signs over time as a function ofnicotine plasma concentration.

DESCRIPTION OF THE INVENTION

The invention provides a composition and a method for delivery of apharmaceutical agent. In particular, the invention provides apharmaceutical formulation for enhanced transmucosal delivery of anionizable pharmaceutically active substance at or near physiological pH.Transmucosal delivery includes the oral mucosa, esophagus,gastrointestinal tract including the stomach and colon, lungs, rectum,sinuses, eyes, urinary tract and the linings of the female reproductiveorgans. The physiological pH of these various membranes variesconsiderably. The physiological pH of the gastrointestinal tractincreases along its length from about pH 1 in the stomach to pH 8 in thecolon. Saliva has a pH around 6.8. The pH of nasal fluids range fromabout pH 5.5 to 6.5. The pH of the vagina is around 4.5. The inventionis designed to provide transmucosal delivery in the pH range specific tothe target mucosal tissue to avoid local irritation. Transmucosalabsorption, as embodied in this invention, is not dependent on pH. Thisis unlike the prior art that requires that the pH be adjusted, typicallyby the use of buffers, to insure that the ionizable pharmaceutical agentis predominately in its freebase or free acid form for optimaltransmucosal delivery. Transmucosal delivery of the ionizablepharmaceutical, as embodied in this invention, only requires thedevelopment of a hydration and dielectric gradient. The presentinvention comprises a pharmaceutical formulation that is capable ofrapidly delivering a pharmaceutical agent into the mucosal tissue or thethrough the mucosal tissue into the circulatory system. For example thepharmaceutical agent may be absorbed through the oral mucosal tissue forsystemic delivery.

The invention further provides a process for the production, and amethod of use, of such a formulation. More specifically, the inventionprovides a high thermodynamic activity lipophilic association (LA) of anionizable pharmaceutical agent paired with a lipophilic agent havingionic character opposite to that of the pharmaceutical agent, such thatthe association is a liquid or is solubilized in a lower-than-waterdielectric solvent. As used herein, the term “high thermodynamicactivity” means that the lipophilic association or lipophilicassociation solvate is in a liquid state at room temperature. The LAbeing a liquid state, or solubilized, is at high thermodynamic activitysuch that drug dissolution is no longer rate limiting to transmucosalabsorption. Further, the invention provides for formulating the highthermodynamic activity LA into a lower-than-water dielectric dosageform, which upon hydration results in an increasingly higher dielectricgradient. This provides the driving force for enhanced delivery of thelipophilized ionizable pharmaceutical agent through the mucus and intosystemic circulation at or near physiological pH.

The invention provides, inter alia, a process for making a transmucosaldrug delivery system for an ionizable pharmaceutical agent by use of alipophilic species having a charge, when ionized, opposite that of theionized pharmaceutical agent. It is the applicants present understandingthat a lipophilic association according to the invention may be, forexample, prepared according to the outline below. That is, for a basicionizable functional group on an ionizable pharmaceutical agent that isnot ionized (deprotonated), the corresponding acidic lipophilic speciesis also not ionized (protonated). For a basic ionizable group on aionizable pharmaceutical agent that is ionized (protonated), thecorresponding acidic lipophilic species is also ionized (deprotonated).In like manner, for an acid ionizable functional group on an ionizablepharmaceutical agent that is not ionized (protonated), the correspondingbasic lipophilic species is also not ionized (deprotonated). For a acidionizable group on a ionizable pharmaceutical agent that is ionized(deprotonated), the corresponding basic lipophilic species is alsoionized (protonated).

For a basic drug, a lipophilic species according to the invention is,for example, fatty acid or another lipophilic species. For a basic drug,a lipophilic species according to the invention may, for example, be oneor more of the following fatty acids, or long-chain alkyl sulfonicacids, or a long-chain alkyl sulfuric acids: caproic, caprylic, capric,lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric,myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic,linolenic, licanic, arachidonic and/or clupanadonic.

For an acidic drug, a lipophilic species according to the invention is,for example, a fatty amine or another lipophilic species. For an acidicdrug, a lipophilic species according to the invention is cetrimide,oleamidopropyl dimethylamine, didecyldimethyl ammonium chloride,quaternary surfactants, cetylpyridinium chloride, hexetidine,benzalkonium chloride and the following fatty amines and acid amides:caproic, caprylic, capric, lauric, myristic, palmitic, stearic,arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic,gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonicand/or clupanadonic.

A formulation according to the invention contains an ionizable drug andan oppositely charged lipophilic species, to form the lipophilicassociation. The LA may require, if not already at a high thermodynamicactivity liquid state, the use of lower-than-water dielectric solvent inorder to prepare a LA-solvate that has high thermodynamic activity.Examples of appropriate lower-than-water dielectric solvents includeethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,tributyl citrate, polyethylene glycols, propylene glycol, bisabolol,glycerin, mineral oil, ethyl oleate, fatty acid esters, squalane, animaloils, vegetable oils, hydrogenated vegetable oils, isopropyl myristate,isopropyl palmitate, glycofurol, terpenes, essential oils, alcohols,polyols, or silicone fluids.

A formulation according to the invention contains an ionizable drug, anoppositely charged lipophilic species, and an excipient, for example, awater-soluble excipient, to lower the local delivery area's dielectricconstant, which is more favorable for association between thepharmaceutical agent and the lipophilic species in this lipophilicassociation. Examples of appropriate water-soluble excipients include asugar, a polyol, an alcohol, a saccharide, a polysaccharide, glycerin,propylene glycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin,triethyl citrate, tributyl citrate, a dextrate, dextrin, dextrose,fructose, lactitol, lactose, erythritol, maltose, maltitol,maltodextrin, polydextrose, trehalose, mannitol, polyethylene glycol,sorbitol, sucrose and/or xylitol.

While the invention is not to be limited by theory, it is theapplicant's understanding that, as water from the local deliveryenvironment hydrates the high thermodynamic activity, lipophilicassociation, lower-than-water dielectric formulation according to theinvention, a hydration and dielectric gradient is formed that providesthe driving force for delivery of the lipophilized ionizablepharmaceutical agent through the mucosa and into systemic circulation.

Surprisingly, it has been found that, in one embodiment, i.e., anicotine sublingual/buccal tablet, a tablet containing a LA preparedwith nicotine and oleic acid at a 1:1 molar ratio is effective inproviding a rapid, bolus dose of nicotine after sublingualadministration. In the art, to enhance delivery, many formulationsrequire a molar ratio of oppositely charged species to activepharmaceutical agent of 50:1 or greater (M. Trotta, E. Urazio, E. Peiraand C. Pulitano, “Influence of ion pairing on topical delivery ofretinoic acid from microemulsions”, J. Control Release, 2003, Vol. 86,pp 315-321).

Further, in a nicotine sublingual/buccal tablet embodiment of theinvention prepared with nicotine and oleic acid, the LA is a liquid witha pH in water of about 5.5 to 7.5, depending on the amount of the oleicacid present. Delivery is as rapid, and possibly more rapid, at lowerpHs, the acidity being determined by any excess oleic acid over thatneeded for formation of the LA. However, excessive acidity is notnecessary. Lower-than-physiological pHs would result if excessiveamounts of oleic acid were needed for transmucosal delivery of theionizable pharmaceutical agent. This attests to the efficiency of theinvention. Further, at the pH range of this delivery system, nicotinepredominately in the ionized form. Such efficient delivery at a pH wherenicotine is ionized is surprising, because ionized pharmaceutical agentstypically have very poor transmucosal delivery (Beckett and Hossie:Buccal Absorption of Drugs, in Handbook of Experimental Pharmacology,ed. B. B. Brodie and J. R. Gillette; Springer-Verlag, Berlin (1971), Ch.3, and H. R. Leipold and E. Quadros: Nicotine Permeation Through BuccalCultures, in Proceed. Intern. Symp. Control. Rel. Bioact. Mater.,Controlled Release Society, 20 (1993), 242-243).

When a nicotine formulation is prepared according to the presentinvention, a rapid, bolus delivery of nicotine results from sublingualadministration of the formulation in the physiological pH range ofsaliva, where nicotine's predominant form is ionized. This is among theadvantages that a formulation according to the invention possesses overother known formulations. In general, transmucosal and transdermal drugdelivery systems for ionizable pharmaceutical agents resort to using thefree-base or free-acid form of the drug to obtain the desired level ofdrug permeation. Delivery of the free-base or free-acid form can causethe local delivery area's pH to be far outside the normal range of thelocal delivery area's customary physiological pH. This pH perturbationcan result in local tissue irritation and cell death. By virtue of theinherent capacity of a formulation according to the invention to deliverionizable pharmaceutical agents at or near physiological pH, delivery ofa ionizable pharmaceutical agent according to the inventionsignificantly reduces local tissue irritation and cell death whencompared with delivery of other formulations. For example, delivery ofnicotine free-base could cause a transient increase in local deliveryarea pH to 10 or above, a pH known in the art to be caustic. Indeed, oneof the side effects of the sublingual nicotine tablet MICROTAB™ is anoral ulcer in the delivery area.

Transmucosal drug delivery according to the invention includes interalia certain preparative steps. According to the invention, an ionizablepharmaceutical agent is prepared into a lipophilic association (LA) bypairing with a lipophilic species that bears, when ionized, an oppositecharge to that of the ionized pharmaceutical agent. In selecting thelipophilic species, efforts are made to ensure that the LA is at highthermodynamic activity, i.e. produces a liquid at room temperature. Ifthis is not possible the LA is solvated in a lower-than-water dielectricsolvent to produce a high activity, liquid LA-solvate. Further, the LAor LA-solvate is formulated so that when placed in water results in asolution pH at or near physiological pH of the targeted mucosal tissue.The LA or LA-solvate is formulated into a dosage form that on contactwith water results in an increasing hydration and dielectric gradient,providing a driving force for transmucosal delivery of the lipophilizedionizable pharmaceutical agent. This can be accomplished by including awater-soluble excipient that has a lower dielectric constant than wateror that, when solubilized in water, lowers the solution's dielectricconstant from that of water.

The invention possesses a number of advantages over known formulations.The invention's lipophilic, high thermodynamic activity LA formulationsprovide for improved transmucosal drug absorption. First, dissolution ofthe pharmaceutical agent is no longer rate limiting to transmucosalabsorption, i.e. the ionizable pharmaceutical agent is already dissolvedbeing a liquid or in solution as the LA or LA-solvate respectively.Second, being in a liquid state the LA is at high molecularthermodynamic activity. Third, due to the lipophilic species used in theformation of the LA, it has greater affinity to lower-than-waterdielectric environments such as cell membranes. The combination of ahigh thermodynamic activity liquid state, with the drug being insolution so as dissolution is not rate limiting, and the lipophilicityof the LA, driven by development of an increasing hydration anddielectric gradient as water enters the lower-than-water dielectricdosage form, provides optimal conditions for delivery of an ionizablepharmaceutical agent through the mucosa and into systemic circulation. Afurther advantage that the invention provides is transmucosal drugdelivery at or near physiological pH. Previously known transmucosaldelivery systems for ionizable pharmaceutical agents resort to using thefree-base or free-acid forms of the drug substance to providetransmucosal drug permeation. In such cases the local delivery area pHcan be far outside the range of physiological pH, resulting in localtissue irritation and cell death.

A formulation according to the invention is embodied in any of a widevariety of different dosage forms, such as buccal tablet, sublingualtablet, oral capsule, oral tablet, nasal spray, buccal or vaginal spray,liquid/semisolid, aerosol for nasal, buccal or pulmonary delivery,patch, lozenge, gum, lollypop, film, strip, paper, suppository, pessaryor other dosage forms using manufacturing techniques familiar to oneversed in the art of formulating and processing pharmaceutical dosageforms. A manufacturing technique according to the invention includes anyof the processes of direct tablet compression, wet or dry granulation,co-melt, dry powder blends, molding, spray-congealing, powder layering,tableting, encapsulating, spray-drying, spheronization, triturates,lyophilization, freeze drying, microencapsulation, troching, pelleting,aerosolizing, liquid or semisolid preparation.

In one embodiment of the present invention, a process of direct powderblends is used to create a solid dosage form. The process of directpowder blends can be outlined as weighing and blending of severalingredients and either encapsulating or compressing the blend intotablet. This is the process that is used in the examples given herein asembodiments.

In one embodiment of the present invention, a process of wet granulationis used to create a solid dosage form. The process of wet granulationcan be outlined as several steps: weighing and blending of severalingredients in the presence of solvent(s), drying the mixture into asolid, and milling the solid to proper size.

In the weighing and blending step of wet granulation, proper amounts ofdrug and lipophilic species and solvent are mixed thoroughly. Additionalingredients may be added to facilitate the mixing of the ingredients.The end result of this step is a finely blended mixture in which thedrug and the lipophilic agent are mixed.

In another embodiment of the present invention, a process of co-meltingis used. In this process, the LA is heated with a low meltingwater-soluble excipient, e.g. polyethylene glycol 6000. In its meltedstate, the excipient can act as a solvent into which the LA is dissolvedor dispersed. The mixture of LA and excipient is then cooled andsolidified. The solid solution of LA and excipient will be furtherprocessed into compressible powder. Other ingredients may also be addedto the co-melted powder to complete the drug formulation.

In yet another embodiment of the present invention, a process offreeze-drying is used. In this process, the LA is dissolved or dispersedin water with a water-soluble powder, e.g. mannitol. The solution isquickly frozen. The frozen solid is then put into a vacuum chamber wherethe water is removed from the solid via sublimation. The resultingpowder is a solid carrier of LA on a water-soluble excipient.

In yet another embodiment of the present invention, a process of spraydrying is used. In this process, the LA is dissolved or dispersed in asolvent with an excipient. The solution or dispersion is then sprayedinto a chamber. The solvent is evaporated while the droplets are in theair. The result is a fine powder consisting of the LA on carrierexcipient.

There are many other processes for making the final dosage form. Theselection of the process will mainly depend on the LA or LA-solvate andthe final dosage form most suitable for treatment of the diseased state.

One embodiment of the invention provides a rapid, bolus dose of anionizable pharmaceutical agent transmucosally and is formulated asliquid/semisolid or as a rapidly dissolving dosage form. Furtherembodiments of the invention provides sustained, delayed and pulsatiledrug delivery. In the case of rapid bolus administration, the dosagefrom dissolves and releases the ionizable pharmaceutical agentrelatively quickly, such as within 30 minutes. A sustained releaseformulation provides a slower delivery of the ionizable pharmaceuticalagent from the dosage form. A delayed release dosage form provides aperiod of time after administration in which no drug delivery occurs,e.g., enteric or colonic delivery systems. A pulsatile releaseformulation provides repeated bolus delivery of the ionizablepharmaceutical agent from the dosage form. Given the description of theinvention contained in this application, it will be apparent to oneskilled in the art how to prepare any such dosage form.

To treat a subject, the formulation, is administered by oral,sublingual, buccal, vaginal, rectal, pulmonary, ophthalmic, orintranasal route. Formulations will contain an effective amount of theactive ingredient in a LA or LA-solvate. The effective amount issufficient to treat a disease state in the target mammal. The effectiveamount is readily determined by one skilled in the art. The activeingredient may typically range from about 1% to about 95% (w/w) of thecomposition, or even higher or lower if appropriate. The quantity to beadministered depends upon factors such as the age, weight and physicalcondition of the animal or the human subject. The quantity also dependsupon the degree of activity desired. Effective dosages can be readilyestablished by one of ordinary skill in the art through routine trialsestablishing dose response curves. The subject is treated byadministration of the formulation in one or more doses. Multiple dosesmay be administered as required.

Intranasal formulations may include vehicles that neither causeirritation to the nasal mucosa nor significantly disturb ciliaryfunction. Diluents such as propylene glycol or polyethylene glycol orother known substances can be employed with the subject invention. Thenasal formulations may also contain preservatives such as, but notlimited to, chlorobutanol and benzalkonium chloride.

Oral preparations may be in the form of, for example, aqueous solutionusing excipients to lower dielectric constant to less than water or oilysuspension, solutions, emulsions, syrups or elixirs, or may be presenteddry in tablet or capsule form or a product for reconstitution with wateror other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, lower-than-water dielectric excipients, non-aqueous vehicles(which may include edible oils), or preservative.

Ionizable Pharmaceutical Agent. A pharmaceutical agent according to theinvention is an ionizable drug substance used for diagnosis, prevention,control, or treatment of a physiological, pathological or psychologicalcondition. It is understood that a considerable variety of drug classesand specific drugs are useful as a pharmaceutical agent according to theinvention. A pharmaceutical agent according to the invention may be, forexample, a member of any of the following classes of drugs:antihypertensive agents, analgesics, antidepressants, opioid agonist,anesthetics, antiarrhythmic, antiarthritics, antispasmodics, ACEinhibitors, decongestants, antibiotics, antihistamines, anti-anginal,diuretics, anti-hypotensive agents, anti-Parkinson agents,bronchodilators, oxytocic agents, anti-diuretics, anti-hyperglycemics,antineoplastics and immunosuppresents agents, antiemetics,anti-infectives, antifungals, antivirals, antimuscarinics, antidiabeticagents, antiallergy agents, anxiolytics, sedatives, antipsychotics, bonemodulating agents, cardiovascular agents, cholesterol lowering drugs,antimalarials, antiepileptics, antihelmintics, agents for smokingcessation, cough suppressants, expectorants, mucolytics, nasaldecongestants, dopaminergics, gastrointestinal agents, muscle relaxants,neuromuscular blockers, parasympathomimetics, prostaglandins,stimulants, anorectics, thyroid and antithyroid agents, hormones,antimigrane agents, antiobesity, and non-steroidal anti-inflammatoryagents. In an embodiment, a pharmaceutical agent according to theinvention is a dihydroergotamine, fentanyl, sufentanil, lidocaine,alfentanil, lofentanil, carfentanil, pentobarbital, buspirone,ergotamine, bisphosphonates, alendronic acid, nalbuphine, bupropion,metformin, diethylcarbamazine, tramadol, amoxicillian, gabapentin,econazole, aspirin, heparin and its derivatives, prostaglandins,methylsergide, ergonovine, endorphin, enkephalins, oxytocin, opiate,barbiturates, albuterol, atropine, scopolamine, selegiline, timolol,nicotine, cocaine, novocaine, amphetamine, caffeine, clorazepic acid,methylphenidate, chlorpromazine, ketamine, epinephrine, estropipate,naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol,isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne,loratadine, chloropheniramine, clonidine, and/or tetracaine.

Lipophilic Species. A lipophilic species according to the inventionpossesses, when ionized, a charge opposite that of an ionizablepharmaceutical agent according to the invention. A lipophilic speciesaccording to the invention combines with the pharmaceutical agent toform a high thermodynamic activity, low dielectric constant, lipophilicassociation. In an embodiment, a pharmaceutical agent and a lipophilicspecies are mixed together in about a 1:1 molar ratio. In a furtherembodiment, an ionizable pharmaceutical agent having more than oneionizable group may require mixing with an equal molar ratio ofoppositely charged lipophilic species for each ionizable group. In yet afurther embodiment, a pharmaceutical agent itself bears oppositelycharged ionizable groups, such as in the case of a peptide or a protein,and may be mixed with both anionic and cationic lipophilic species. In aparticular embodiment, a molar excess of a lipophilic species is mixedwith the ionizable pharmaceutical agent, lowering the dielectricconstant and improving solubility of the LA.

For a drug having basic functional groups, a lipophilic speciesaccording to the invention is an anion (when ionized), for example, afatty acid. For drugs with basic functional groups, a lipophilic speciesaccording to the invention is one or more of the following fatty acids,long-chain alkyl sulfonic acids, or long-chain alkyl sulfuric acids:caproic, caprylic, capric, lauric, myristic, palmitic, stearic,arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic,gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonicand/or clupanadonic. For drugs with acidic functional groups, alipophilic species according to the invention is a cation (whenionized), for example, fatty amines. For drugs with acidic functionalgroups, a lipophilic species according to the invention is one or moreof the following: cetrimide, oleamidopropyl dimethylamine,didecyldimethyl ammonium chloride, quaternary surfactants,cetylpyridinium chloride, hexetidine, benzalkonium chloride, and/or oneor more of the following fatty amines and acid amides: caproic,caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,ricinoleic, linoleic, linolenic, licanic, arachidonic and/orclupanadonic. Drugs with multiple functional groups would requiremixtures of these lipophilic species.

LA Solvent. A lipophilic species according to the invention is mixedwith a pharmaceutical agent according to the invention to form a highthermodynamic activity, low dielectric, lipophilic LA. In an embodiment,the LA thus formed is a liquid and therefore is already at highactivity. In a further embodiment, the LA is solubilized in order toattain a high activity thermodynamic state, i.e., a liquid state at roomtemperature. In a particular embodiment, a formulation according to theinvention contains a molar excess of one or more lipophilic species forsolubilizing and providing a low dielectric liquid environment for theLA. In a further particular embodiment, a formulation according to theinvention contains a lower-than-water dielectric solvent other than alipophilic species. In an embodiment, a lower-than-water dielectricsolvent other than a lipophilic species according to the invention isethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,tributyl citrate, a polyethylene glycol, propylene glycol, bisabolol,glycerin, mineral oil, ethyl oleate, a fatty acid ester, squalane, ananimal oil, a vegetable oil, a hydrogenated vegetable oil, isopropylmyristate, isopropyl palmitate, glycofurol, a terepene, an essentialoil, an alcohol, a polyol, or a silicone fluid.

Solid Carrier. In an embodiment, a formulation according to theinvention contains a solid carrier. A liquid LA or LA-solvate accordingto the invention is adsorbed or absorbed onto a solid carrier to improveprocessing. When an ingredient is a liquid it is typically necessary toconvert it into a solid before blending it with other powders to preparetablets, capsules or other solid dosage forms. The liquid is typicallyof an oily nature and can be adsorbed onto the surface of a solid.Adsorption, being a surface phenomenon, is influenced by the availablesurface area on the solid. Thus, the most efficient adsorbents areusually very small particles. In an embodiment, an adsorbent accordingthe invention may be microcrystalline celluloses, cellulose powder,silicified microcrystalline celluloses (PROSOLV 50, PROSOLV 90HD),silicas (ZEOPHARM 5170, AEROPERL 300, SYLOID 244FP, SYLOID 63FP, SYLOID72 FP), clays, talc, starches, pregelatinized starches, calciumcarbonate, and magnesium carbonate. In one embodiment, a solid carrierfor a liquid LA according to the invention is a cyclodextrin or asubstituted cyclodextrin. These materials form inclusion complexes withlipophilic molecules on a 1:1 molar ratio. Cyclodextrins are “bucketlike” molecules, with a ridged structure and a central cavity. Theinternal surface of the central cavity is lipophilic, while the outsidesurface is hydrophilic. This arrangement allows the cyclodextrin toharbor a guest molecule within the cavity, forming an inclusion complexthat is water-soluble. Thus, this mechanism of solidification is byabsorption.

Water-Soluble Excipient. In an embodiment, a formulation according tothe invention contains a water-soluble excipient. A variety ofexcipients are useful as the water-soluble component of the invention,the selection being based on the delivery system. In an embodiment, thewater-soluble excipient can be a water-soluble LA solvent, e.g.,propylene glycol for use in a liquid dosage form. In an embodiment, thewater-soluble excipient can be a tablet diluent, e.g., mannitol for asolid dosage form. The development of a gradually increasing hydrationand dielectric gradient in the dosage form is most favorable fortransmucosal delivery of an ionizable pharmaceutical agent according tothe invention. Hence, in an embodiment, a water-soluble excipientaccording to the invention is one or more of the following: a sugar, apolyol, a alcohol, a saccharide, a polysaccharide, glycerin, propyleneglycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin, triethylcitrate, tributyl citrate, a dextrate, a dextrin, dextrose, fructose(ADVANTOSE FS 95), lactitol (FINLAC DC), lactose, erythritol, maltose,maltitol, a maltodextrin, a polydextrose, trehalose, mannitol (PEARLITOL300 DC, PEARLITOL 400 DC, PEARLITOL 500 DC, MANNOGEM 2080, MANNOGEM EZ,PARTEK M200, PARTEK M300), a polyethylene glycol, sorbitol, sucrose andxylitol (XYLITOL 200, XYLITOL 300).

Other Excipients. In an embodiment, another excipient, chosen to enhanceprocessability, form, function or appeal of the formulation is includedin a formulation according to the invention. In such an embodiment,another excipient according to the invention is a buffering agent (suchas phosphate, carbonate, tartrate, borate, citrate, acetate, and maleatebuffers), colorant, flavoring, solvent and co-solvent, coating agent,binder, diluent, carrier, disintegrant, glident, lubricant, opacifyingagent, humectant, granulating agent, gelling agent, polishing agent,suspending agent, sweetening agent, anti-adherent, preservative,emulsifying agent, antioxidant, levigating agent, plasticizer,surfactant, tonicity agent, viscosity agent, enteric agent and coating,controlled-release agent and coating, wax, wetting agent, thickeningagent, suppository base, stiffing agent, stabilizing agent, solubilizingagent, sequestering agent, ointment base, oleaginous vehicle,film-forming agent, essential oil, emollient, dissolution enhancer,dispersing agent, and/or cryoprotectant or combinations thereof.

EXEMPLARY EMBODIMENTS Sublingual/Buccal Tablets

It will be readily understood that the components, formulations,processes, and methods of use of the present invention, as generallydescribed herein, are arranged and designed in a wide variety ofdifferent dosage forms and formulations. Thus, the following moredetailed description of the embodiments of the formulation and methodsof use of the present invention is not intended to limit the scope ofthe present invention, as claimed, but merely represents one of thedosage form embodiments of the invention, e.g. a sublingual/buccaltablet.

Example I Nicotine

In an embodiment, a buccal/sublingual tablet formulation according tothe invention is useful in nicotine replacement therapy (NRT). Certaincommercially available products for NRT in smoking cessation, such aspatches, gum, and lozenges, do not provide for the rapid rise or peaknicotine plasma levels obtained by smoking. Certain other products, suchas nasal sprays, inhalers, and certain sublingual tablets, that attemptto provide nicotine plasma levels similar to smoking a cigarette, resultin local irritation.

Pomerleau (Ann. Behav. Med. 1998, Vol. 36, 158-163) listed criteria fora successful NRT: 1) the method should be safe and easy to use; 2)specific doses should be accurately and reproducibly delivered; 3) thepharmacokinetics should resemble those of cigarette smoking. Judgingfrom the very limited efficacy of the current commercial NRTs (typicallyless than 20%), current commercial NRTs are not meeting the Pomerleaucriteria.

However, an embodiment of the present invention did meet the Pomerleaucriteria. One embodiment of the present invention provides a convenient,small, round sublingual/buccal tablet useful for NRT. Such a tabletrapidly dissolved under the tongue or dissolved more slowly in thebuccal cavity between the gums and cheek. Further, it did not produceulcers in the mouth, which is one of the undesired side effects of otherformulations that use nicotine in its free base form. It was alsoconvenient and easy to use and is a socially acceptable delivery system.It is much more like taking a breath mint, unlike nasal sprays orinhalers. Further, such a tablet reproducibly provided a rapid bolus ofnicotine after sublingual administration. Hence a sublingual/buccaltablet according to the invention meets the Pomerleau criteria and ismore successful at helping smokers quit cigarettes than the currentlymarketed products.

In one embodiment, the invention provided a 2 mg strength nicotinesublingual/buccal tablet having a total tablet weight around 50 mg andnominal dimensions of about 0.55 cm in diameter and a thickness of about0.15 cm. In such an embodiment, the ionic pharmaceutical agent accordingto the invention contained nicotine and a lipophilic species. Thelipophilic species was oleic acid. The molar ratio of lipophilic speciesto ionic pharmaceutical agent was not less than about 1:1. However, amolar excess of the lipophilic species, in this example oleic acid, maybe used, e.g., 1.2:1, but is not limited to this ratio. This LA is aliquid at room temperature. In order to convert the LA into a flowablepowder suitable for use in direct compression tableting required the useof an adsorbent/absorbent, such as silica. In order to manufacture arapidly disintegrating, directly compressible tablet other excipientswere needed. For example, the diluent may be the water-soluble, directcompression tableting excipient mannitol. A disintegrant is included torapidly break the tablet apart upon administration. An exemplarydisintegrant is sodium starch glycolate. An exemplary tablet lubricantis sodium stearyl fumarate. A quantitative formulation is given in TableI.

TABLE I 2 mg Nicotine Sublingual/Buccal Tablet Formulation INGREDIENTAMOUNT (mg/tablet) Nicotine 2.0 Oleic Acid 3.5 Silica 4.0 Mannitol 38.5Sodium Starch Glycolate 1.5 Sodium Stearyl Fumarate 0.5 Total TabletWeight 50.0

A method of manufacture for a sublingual/buccal tablet according to theinvention is a suitable method known in the art, such as the addition ofthe nicotine LA or LA-solvate to premanufactured tablets, coldcompressions with inert fillers and binders, direct tablet compressionblends, direct powder blends, wet or dry granulations, molding,lyophilization, microencapsulation, co-melt, freeze drying,spray-congealing, spray-drying, spheronization, triturates, troching,powder layering, pelleting, encapsulation. An exemplary method ofmanufacture is outlined below and schematically in FIG. 1.

STEP 1: Mix nicotine and oleic acid together until homogeneous, to forma nicotine LA.

STEP 2: Blend the nicotine LA with silica until homogeneous to form anicotine LA silica carrier blend.

STEP 3: Add the nicotine LA silica carrier blend to mannitol and sodiumstarch glycolate and blend until homogeneous to form a further blend.

STEP 4: Add sodium stearyl fumarate to the further blend and blend untilwell lubricated to form a lubricated blend.

STEP 5: Compressing the lubricated blend into tablets using 7/32″ roundtooling.

Method of packaging. The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining nicotine stability. Exemplarypackaging methods and materials include, but are not limited to, blisterpackaging in a foil/foil, foil/Acrylonitrile,foil/Polychlorotrifluoroethylene laminates.

Comparative dissolution. Drug dissolution is a prerequisite to drugabsorption and clinical response for almost all drugs given orally. (G.L. Amidon, H. Lennemas, V. P. Shah, J. R. Crison, “A Theoretical Basisfor a Biopharmaceutical Drug Classification: The Correlation of in VitroDrug Product Dissolution and in Vivo Bioavailability,” Pharm. Res. 1995,Vol. 12, No. 3, pp 413-420.) Dissolution is considered an in vitrotechnique that gives good correlation to a product's in vivoperformance. A drug must first be released from the delivery system inorder to be available for absorption. Therefore, tablets having a fasterdissolution would be expected to have faster absorption in vivo. FIG. 2presents the dissolution results of the nicotine sublingual/buccaltablet, the embodiment of the invention as presented herein, and twonicotine commercial products, i.e., a lozenge (COMMIT™ and a sublingualtablet MICROTAB™). Dissolution was conducted in 900 ml of D.I. water at50 RPM using USP Apparatus 2. Samples were pulled at 2, 5, 10, 20, 30,40 and 60 minutes, and analysis was by HPLC.

As can be seen from the dissolution profiles, the sublingual/buccaltablet released over 90% of the nicotine in the tablet within 10minutes. This rapid release of nicotine corresponded to typical plasmanicotine levels obtained from smoking a cigarette, which peak in about10 minutes (WO 03/055486 A1). The lozenge COMMIT™ shows a very slowprofile releasing only 35% of the dosage at the end of 60 minutes. Theother sublingual tablet, MICROTAB™, takes about 30 minutes to reach thesame level that the embodied invention given herein reached within 10minutes, i.e., 90% of the dosage dissolved.

The other products fail to provide rapid nicotine release, and thereforecannot provide a nicotine plasma level comparable to what a personobtains from smoking a cigarette. The present invention as embodiedherein did provide rapid nicotine release. Indeed, more than 90% of thenicotine in the tablet was dissolved and available for transmucosalabsorption within 10 minutes. It should be noted that the pH of thedissolution media obtained after dissolution of the sublingual/buccaltablets as embodied in this invention was 6.2. This is very similar tothe pH of saliva, which is general recognized as being around 6.8. At apH of 6.8 only about 10% of the nicotine is in the free base form.Others have indicated that in order to promote absorption of nicotinethrough the oral mucosa, the pH of the saliva must be increased so thatnicotine will be predominately in the free base form (WO 03/055486 A1).The present invention provides for nicotine transmucosal absorption inacidic conditions similar to the physiological pH of the saliva. Othersindicated that such a low pH nicotine transmucosal delivery would not beefficacious.

In Vivo Data: Two male volunteers and one female volunteer, all formersmokers, placed the nicotine sublingual tablet, as embodied herein,under the tongue and left it undisturbed. Immediately uponadministration a tingling sensation was very apparent in the area wherethe sublingual tablet was placed. Shortly thereafter, i.e., within a fewminutes, the physiological effects of nicotine were very apparent to allthree volunteers. This included being light-headed, dizzy, a warningsensation and an increase in heart rate. In all three volunteers, thesymptoms peaked within 10 minutes and the tablets were totally dissolvedin less than 5 minutes. Interestingly, the usually overwhelming acridtaste of nicotine was not apparent. Instead there was a slightly bittertaste that was complimented by the sweet taste of mannitol. Within 30minutes all volunteers felt normal. All three volunteers stated that thenicotine sublingual tablet, as embodied herein, provided a bolus ofnicotine that was similar to that obtained from smoking a cigarette.

Method of Use: In an exemplary embodiment, a buccal/sublingual tabletformulation according to the invention is useful in nicotine replacementtherapy (NRT). This therapy is designed to allow smokers to quit smokingby providing nicotine in a non-carcinogenic delivery system, i.e.,without tars. In a typical treatment regiment, the smoker starts byplacing a 2 or 4 mg nicotine sublingual tablet under the tongue andleaving it undistributed until dissolved, typically within 5 minutes,whenever there is an urge to smoke. In one embodiment, about 10 to 30sublingual tablets are used per day. After a period of several weeks,the dosage is lowered to 2 mg or 1 mg (depending on the startingstrength) then to 0.5 mg. Eventually, a placebo is used, if required.This gradual reduction in nicotine content helps wean the smoker off thedesire for nicotine. This is usually supplemented with counseling. Thetablets of the present invention can also be used by smokers when it isnot acceptable for them to smoke, e.g., when they are in an airplane.The dosage range for this embodiment may be from 0.5 mg to 5 mg ofnicotine.

Example II Epinephrine

Epinephrine (adrenaline) is commonly given by subcutaneous orintramuscular injection for anaphylactic shock, allergic reactions andacute asthmatic attacks. The usual dosage is 300 .mu.g, givenintramuscularly by use of an auto-injector. Patients with a history ofsevere allergic reactions to insect bites or stings, foods, drugs, andother allergens, as well as idiopathic and exercise induced anaphylaxis,are supplied with auto-injectors for intramuscular self-administration.This is the preferred treatment for serious allergic reactions. Anembodiment according to the invention, an epinephrine sublingual/buccaltablet as described below, has several advantages over the currenttherapy. First, the invention as embodied herein is convenient,non-invasive and painless to administer. Further, epinephrine is alsounstable in light and is readily oxidized; an embodiment according tothe invention, as described below, being a solid-state product ratherthan liquid preparation, provides better stability.

In such an embodiment, the invention provides a 300 .mu.g strengthepinephrine sublingual/buccal tablet having a total tablet weight around50 mg and nominal dimensions of about 0.55 cm in diameter and athickness of about 0.15 cm. In such an embodiment, the ionicpharmaceutical agent according to the invention contains epinephrine andthe lipophilic species with which it is combined (such as oleic acid),the molar ratio of the lipophilic species to ionic pharmaceutical agentbeing not less than about 1:1. However, a molar excess of the lipophilicspecies, in this example oleic acid, may be used, e.g., 1.2:1.Embodiments are described herein. In certain embodiments, the LA mayrequire the use of a solvent to stabilize or solubilize the LA, e.g.,ethyl oleate and polyethylene glycol 400. Embodiments are describedherein. In certain embodiments, the liquid LA or LA-solvate requires theuse of an adsorbent/absorbent in order to convert it into a flowablepowder suitable for use in direct compression tableting (such assilica). Other excipients are in some circumstances useful in order tomanufacture a rapidly disintegrating, directly compressible tablet (suchas the water-soluble, direct compression tableting excipient mannitol).In order to rapidly break the tablet apart upon administration, adisintegrant is used. In one embodiment the disintegrant is sodiumstarch glycolate. An exemplary tablet lubricant is sodium stearylfumarate. Exemplary embodiments are provided in Table II.

TABLE II 300 μg Epinephrine Sublingual/Buccal Tablet Formulations AMOUNTAMOUNT AMOUNT (mg/tablet) (mg/tablet) (mg/tablet) Embodiment EmbodimentEmbodiment INGREDIENT 1 2 3 Epinephrine 0.30 0.30 0.30 Oleic Acid 0.460.46 0.46 Ethyl oleate — 4.74 — Polyethylene glycol 400 — — 4.74 Silica0.55 4.00 4.00 Mannitol 46.69 38.50 38.50 Sodium Starch Glycolate 1.501.50 1.50 Sodium Stearyl Fumarate 0.50 0.50 0.50 Total Tablet Weight50.00 50.00 50.00

Method of manufacture. A method of manufacture for suchsublingual/buccal tablet embodiments may be any suitable method known inthe art including, but not limited to, the addition of the epinephrineLA or LA-solvate to premanufactured tablets, cold compressions withinert fillers and binders, direct tablet compression blends, directpowder blends, wet or dry granulations, molding, lyophilization,microencapsulation, freeze drying, spray-congealing, spray-drying,co-melt, spheronization, triturates, troching, powder layering,pelleting, encapsulation. An exemplary method of manufacture is outlinedbelow and is schematically diagramed in FIG. 3.

STEP 1: Mix epinephrine, oleic acid and any other solvents together toform a solution. STEP 2: Blend the epinephrine LA or LA-solvate withsilica until homogeneous to form a silica carrier blend. STEP 3: Add thesilica carrier blend to mannitol and sodium starch glycolate and mixuntil homogeneous to form a further blend. STEP 4: Add sodium stearylfumarate to the further blend and blend until well lubricated to form alubricated blend. STEP 5: Compressing the lubricated blend into tabletsusing 7/32″ round tooling.

Method of packaging. The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining epinephrine stability. Packagingmethods and materials may include, but are not limited to, blisterpackaging in a foil/foil, foil/Acrylonitrile,foil/Polychlorotrifluoroethylene laminates.

Method of Use: In an embodiment, a buccal/sublingual tablet formulationaccording to the invention is useful in the treatment of severe allergicreactions to insect bites or stings, foods, drugs, and other allergens,as well as idiopathic and exercise induced anaphylaxis. This therapy isdesigned to allow allergic patient to abort a hyper immune response suchas anaphylaxis. The typical treatment regiment starts by placing a 300.mu.g epinephrine sublingual tablet under the tongue and leaving itundistributed until dissolved, typically within 5 minutes, wheneverthere is an allergic reaction. This can be supplemented with additionalsublingual tablets until the allergic response is ameliorated. Thedosage range for this embodiment may vary from 200 ug to 1000 ug.

Example III Fentanyl

Fentanyl transmucosal delivery is first line therapy for management ofbreakthrough cancer pain in patients with malignancies who are alreadytolerant to opioid therapy for their underlying persistent cancer pain.The embodiments as given herein have several advantages over the currenttherapy. First, the current transmucosal therapy uses a lollipop as thedelivery system. The inherent implication and dangers of placing apotent opiate in the form of a candy attractive to children cannot betrivialized. Further, the current therapy takes over 20 minutes to reachmaximum plasma concentrations. Thus pain relief is delayed far longerthan would be desired. Hence the invention provides, in an embodiment, afentanyl sublingual/buccal tablet to rapidly dissolve under the tongue,providing fast onset of action and pain relief for a cancer patient.Further, it is much safer for the family environment than a lollipop,which requires the disposal of potent, opioid-laden delivery systems.

In one embodiment, the invention provides a 200 ug strength fentanylsublingual/buccal tablet having a total weight around 50 mg and nominaldimensions of about 0.55 cm in diameter and a thickness of about 0.15cm. In one embodiment, the ionic pharmaceutical agent is fentanyl andthe lipophilic species with which it is combined is oleic acid. Themolar ratio of the lipophilic species to ionic pharmaceutical agent inthis embodiment is not less than about 1:1. However, a molar excess ofthe lipophilic species, in this example oleic acid, may be used, e.g.1.2:1. Embodiments are described herein. In certain embodiments, the LAmay require the use of a solvent to stabilize or solubilize the LA, e.g.ethyl oleate and polyethylene glycol 400. In certain embodiments, theliquid LA or LA-solvate requires the use of an adsorbent/absorbent inorder to convert it into a flowable powder suitable for use in directcompression tableting. An exemplary adsorbent is a silica Otherexcipients may be used in order to manufacture a rapidly disintegrating,directly compressible tablet. An exemplary diluent is the water-soluble,direct compression tableting excipient mannitol. In order to rapidlybreak the tablet apart upon administration, a disintegrant is used. Anexemplary disintegrant is sodium starch glycolate. An exemplary tabletlubricant is sodium stearyl fumarate. Exemplary embodiments are providedin Table III.

TABLE III 200 μg Fentanyl Sublingual/Buccal Tablet Formulations AMOUNTAMOUNT AMOUNT (mg/tablet) (mg/tablet) (mg/tablet) Embodiment EmbodimentEmbodiment 1 2 3 Fentanyl 0.20 0.20 0.20 Oleic Acid 0.17 0.17 0.17 Ethyloleate — 5.13 — Polyethylene glycol 400 — — 5.13 Silica 0.27 4.00 4.00Mannitol 47.36 38.50 38.50 Sodium Starch Glycolate 1.50 1.50 1.50 SodiumStearyl Fumarate 0.50 0.50 0.50 Total Tablet Weight 50.00 50.00 50.00

Method of manufacture. A method of manufacture for suchsublingual/buccal tablet embodiments may be any suitable method known inthe art including, but not limited to, the addition of the fentanyl LAor LA-solvate to premanufactured tablets, cold compressions with inertfillers and binders, direct tablet compression blends, direct powderblends, wet or dry granulations, molding, lyophilization,microencapsulation, freeze drying, spray-congealing, spray-drying,co-melt, spheronization, triturates, troching, powder layering,pelleting, encapsulation. An exemplary method of manufacture is outlinedbelow and is schematically represented in FIG. 4.

STEP 1: Mix fentanyl, oleic acid and any other solvents together to forma solution. STEP 2: Blend the fentanyl LA or LA-solvate with silicauntil homogeneous to form a silica carrier blend. STEP 3: Add the silicacarrier blend to mannitol and sodium starch glycolate and mix untilhomogeneous to form a further blend. STEP 4: Add sodium stearyl fumarateto the further blend and blend until well lubricated to form alubricated blend. STEP 5: Compressing the lubricated blend into tabletsusing 7/32″ round tooling.

Method of packaging. The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining fentanyl stability. Exemplarypackaging methods and materials include, but not limited to, blisterpackaging in a foil/foil, foil/Acrylonitrile,foil/Polychlorotrifluoroethylene laminates.

Method of Use: In an embodiment, a buccal/sublingual tablet formulationaccording to the invention is useful in the treatment of severebreakthrough cancer pain in patients with malignancies who are alreadytolerant to opioid therapy for their underlying persistent cancer pain.This therapy is designed to allow the cancer patient to self-administerthe treatment. The treatment regiment starts by placing a 200 ugfentanyl sublingual tablet under the tongue and leaving it undistributeduntil dissolved, typically within 5 minutes, whenever there is anoccurrence of breakthrough pain. Depending on the level of opiatetolerance in each patient, other dosage strengths may be used intreatment of each individual patient. The range of dosage strength canbe from 50 ug to 5000 ug.

Example IV Alendronic Acid

Bisphosphonates are potent inhibitors of bone resorption and are used inosteoporosis and Paget's disease of the bone. These are also used in thetreatment of bone metastases and hypercalcaemia of malignancies. Themost commonly used bisphosphonates are alendronic acid, clodronic acidand etidronic acid. The embodiments as given herein have severaladvantages over the current bisphosphonate therapies. First, the currenttherapy is a tablet given by mouth or by IV injection. Oraladministration is associated with a number of severe side effectsincluding oesophagitis, esophageal erosions and ulcerations, dyspepsia,diarrhea, abdominal pain, and peptic ulcers. Further, oralbioavailability is very poor, in the range of 0.4 to 0.7% for alendronicacid and from to 1 to 6% for clodronic and etidronic acids. Whenadministrated with food, bioavailability can be significantly reducedeven to the level of being negligible. For alendronic acid, the usualdaily dosage is 5 to 10 mg for osteoporosis and the dosage for Paget'sdisease is about 40 mg per day. The present invention provides, in oneembodiment, a sublingual/buccal tablet that is designed to rapidlydissolve under the tongue. This avoids the potentially serious sideeffects and the poor and erratic bioavailability observed from oraldelivery.

In one embodiment, a 100 .mu.g strength alendronic sublingual/buccaltablet has a total weight of about 50 mg, and nominal dimensions ofabout 0.55 cm in diameter and a thickness of about 0.15 cm. The ionicpharmaceutical agent in this example is alendronic acid combined withthe lipophilic species oleic acid. Alendronic acid has an aminefunctional group in additional to acid functional groups in addition toacid functional groups. The molar ratio between these two species inthis example is at least about 1:1. However, since alendronic acidcontains two phosphoric acid groups, a lipophilic amine or amide, inthis example hexetidine, may need. The molar ratio is at least about 1:1but may be increased to about 2:1. In certain embodiments, the LA mayrequire the use of a solvent to stabilize or solubilize the LA, e.g.,ethyl oleate and polyethylene glycol 400. Embodiments are describedherein. The LA or LA-solvate may require the use of anadsorbent/absorbent in order to convert it into a flowable powdersuitable for use in direct compression tableting. In one embodiment, theadsorbent is a silica. In order to manufacture a rapidly disintegrating,directly compressible tablet other excipients may be needed. In oneembodiment, the diluent is the water-soluble, direct compressiontableting excipient mannitol. In order to rapidly break the tablet apartupon administration, a disintegrant is used. In one embodiment, thedisintegrant is sodium starch glycolate. In one embodiment, the tabletlubricant is sodium stearyl fumarate. Several embodiments are given inTable IV.

TABLE IV 100 μg Alendronic Acid Sublingual/Buccal Tablet FormulationsAMOUNT AMOUNT AMOUNT AMOUNT (mg/tablet) (mg/tablet) (mg/tablet)(mg/tablet) Embodiment Embodiment Embodiment Embodiment INGREDIENT 1 2 34 Alendronic 0.10 0.10 0.10 0.10 acid Oleic acid 0.12 0.13 0.13 0.13Hexetidine — 0.27 0.27 0.27 Ethyl oleate — — 5.00 — Polyethylene — — —5.00 glycol 400 Silica 0.13 0.35 4.00 4.00 Mannitol 47.65 47.16 38.5138.51 Sodium Starch 1.50 1.50 1.50 1.50 Glycolate Sodium Stearyl 0.500.50 0.50 0.50 Fumarate Total Tablet 50.00 50.00 50.00 50.00 Weight

Method of Manufacture

The method of manufacture for this sublingual/buccal tablet embodimentmay be any suitable method know in the art including, but not limitedto, the addition of the alendronic acid LA or LA-solvate topremanufactured tablets, cold compressions with inert fillers andbinders, direct tablet compression blends, direct powder blends, wet ordry granulations, molding, co-melt, lyophilization, microencapsulation,freeze drying, spray-congealing, spray-drying, spheronization,triturates, troching, powder layering, pelleting, encapsulation. Oneexemplary method of manufacture is outlined below and is schematicallyin FIG. 5.

STEP 1: Mix alendronic acid, oleic acid, and any other the lipophilicspecies or solvents together to form a solution. STEP 2: Blend thealendronic acid LA or LA-solvate with silica until homogeneous to form asilica carrier blend. STEP 3: Add the silica carrier blend to mannitoland sodium starch glycolate and mix until homogeneous to form a furtherblend. STEP 4: Add sodium stearyl fumarate to the further blend andblend until well lubricated to form a lubricated blend. STEP 5:Compressing the lubricated blend into tablets using 7/32″ round tooling.

Method of Packaging: The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining stability. Exemplary packagingmethods and materials include blister packaging in a foil/foil,foil/Acrylonitrile, foil/Polychlorotrifluoroethylene laminates.

Method of Use: In an embodiment, a buccal/sublingual tablet formulationaccording to the invention is useful in the treatment of osteoporosisand Paget's disease of the bone. It can also be used in the treatment ofbone metastases and hypercalcaemia of malignancies. In one embodimentthe treatment regiment starts by placing a 100 .mu.g alendronic acidsublingual tablet under the tongue and leaving it undistributed untildissolved, typically within 5 minutes. The treatment is given once aday. The dosage range for this embodiment may be from 50 .mu.g to 1000.mu.g.

Example V Clorazepic Acid

Clorazepic acid is a benzodiazepine used mainly for the treatment ofanxiety, adjunct therapy for epilepsy and alcohol withdrawal syndrome.It is administered orally, intravenously and intramuscularly. Orally itis typically given in divided doses. The embodiments as given hereinhave several advantages over the current therapies. A patient undergoingalcohol withdrawal will typically exhibit signs of nausea and vomiting.Any orally administrated therapy during times of alcohol withdrawal runsthe risk of being not efficacious as vomiting can eliminate the dosage.Further, for children, geriatric and depilated patients, swallowing atablet can be difficult. Since clorazepic acid is used in the relief ofanxiety for elderly and debilitated patients and also as an adjuncttherapy for epilepsy in children, having a convenient dosage form thatdoes not require swallowing a tablet for administration provides abetter therapy. Another therapy for which benzodiazepines have been usedis for panic attacks. Sublingual clorazepic may be useful in thetreatment of panic attacks, particularly due to its rapid onset ofaction. Panic attacks and agoraphobia could be avoided by administeredthe sublingual tablet just prior to the patient encountering a situationknown to induce such attacks. Further, it could be used at the firstsigns of an attack, due to its rapid absorption, and thereby abort theattack.

Exemplary Embodiment

In one embodiment, a 5.75 mg strength clorazepic acid sublingual/buccaltablet has a total weight around 100 mg, and nominal dimensions of about0.64 cm in diameter and a thickness of about 0.20 cm. The ionicpharmaceutical agent is clorazepic acid combined with the lipophilicspecies hexetidine. The molar ratio between these two species being notless than about 1:1. This LA may also require the use of a solvent. TheLA or LA-solvate may require the use of an adsorbent/absorbent in orderto convert it into a flowable powder suitable for use in directcompression tableting. One exemplary adsorbent for this embodiment is asilica. In order to manufacture a rapidly disintegrating, directlycompressible tablet, other excipients may be needed. In one embodimentthe diluent is the water-soluble, direct compression tableting excipientmannitol. In order to rapidly break the tablet apart upon administrationa disintegrant is used. In one embodiment, the disintegrant is sodiumstarch glycolate. In one embodiment, the tablet lubricant is sodiumstearyl fumarate. Several embodiments, are given in Table V below.

TABLE V 5.75 mg Clorazepic Acid Sublingual/Buccal Tablet FormulationsAMOUNT AMOUNT AMOUNT (mg/tablet) (mg/tablet) (mg/tablet) EmbodimentEmbodiment Embodiment INGREDIENT 1 2 3 Clorazepic acid 5.75 5.75 5.75Hexetidine 6.25 6.25 6.25 Ethyl oleate — 2.00 — Polyethylene glycol 400— — 2.00 Silica 8.00 9.00 9.00 Mannitol 76.00 73.00 73.00 Sodium StarchGlycolate 3.00 3.00 3.00 Sodium Stearyl Fumarate 1.00 1.00 1.00 TotalTablet Weight 100.00 100.00 100.00

Method of Manufacture: The method of manufacture for thissublingual/buccal tablet embodiment may be any suitable method know inthe art including, but not limited to, the addition of the clorazepicacid LA or LA-solvate premanufactured tablets, cold compressions withinert fillers and binders, direct tablet compression blends, directpowder blends, wet or dry granulations, molding, spray-congealing,lyophilization, freeze-drying, microencapsulation, co-melt,spray-drying, spheronization, triturates, troching, powder layering,pelleting, encapsulation. One method of manufacture is outlined belowand is schematically represented in FIG. 6.

STEP 1: Mix clorazepic acid, hexetidine and any other solvents togetheruntil a solution is prepared. STEP 2: Blend the clorazepic acid LA orLA-solvate with silica until homogeneous. STEP 3: Add the clorazepic LAor LA-solvate silica carrier blend to mannitol and sodium starchglycolate and mix until homogeneous. STEP 4: Add sodium stearyl fumarateto the blend from Step 3 and blend until well lubricated. STEP 5: Thelubricated blend from Step 4 is compressed into tablets using ¼″ roundtooling.

Method of Packaging: The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining stability. Exemplary packagingmethods and materials include, but are not limited to, blister packagingin a foil/foil, foil/Acrylonitrile, foil/Polychlorotrifluoroethylenelaminates.

Method of Use: In an embodiment, a sublingual/buccal tablet formulationaccording to the invention is useful in the treatment of alcoholwithdrawal, anxiety or epilepsy. This therapy is designed to allow thepatient to administer the therapy without having to swallow the dosageform. The typical treatment regiment starts by placing a 5.75 mgclorazepic acid sublingual tablet under the tongue and leaving itundistributed until dissolved, typically within 5 minutes. This can besupplemented with additional sublingual tablets during the day,typically three times per day; however, under certain treatmentregiments one tablet at night may be given. For panic attacks andagoraphobia, the patient can administer the sublingual tablet just priorto encountering a panic-inducing situation or at the onset of an attack.The dosage range for this embodiment can be from 2 mg to 12 mg ofclorazepic acid.

In one embodiment, the pharmaceutical composition of the subjectinvention is provided as an oral solid dosage form for buccal orsublingual administration, e.g. films, lozenges, pills and tablets. Inthe following illustrative embodiments, the oral dosage form is providedas a tablet. In the following illustrative embodiments, the treatment isdirected to subjects with tobacco dependence or other indications forwhich nicotine can be used as a therapeutic and wherein increasing theoral absorption and bioavailability, while shortening the onset ofnicotine action is provided.

It is understood by the skilled artisan, that use of the term “about”includes the range as stated, are within what is normally acceptable inthe pharmaceutical industry. The US Pharmacopeia allows a plus and minusrange of 10% in the assay for the active ingredient in most solid dosageforms. The Food and Drug Administration (FDA) has a published Guidancesfor changes in levels of common excipient classes that are consideredunlikely to have any detectable impact on formulation quality andperformance (Guidance for Industry: Immediate Release Solid Oral DosageForms Scale-Up and Post approval Changes: Chemistry, Manufacturing, andControls, In Vitro Dissolution Testing, and In Vivo BioequivalenceDocumentation). Under this Guidance the water-soluble solid excipienthas an allowable change is .+−.5%, for a disintegrant it is .+−.1%, fora lubricant it is .+−.1%. Although the Guidance is not specific for thecomplimentary lipophilic species, co-solvent or adsorbent andconsidering the range for the active is .+−.10%, the value for theseexcipients should be no different than the active as their use in theformulation is directly dependent on the active's level.

As illustrated, tablets are used for the treatment and such tabletscontain from about 0.1 mg to about 5 mg of nicotine, from about 0.15 mgto about 10 mg of a complimentary lipophilic species, illustrated by,albeit not limited to, oleic acid, from about 0.1 mg about 50 mg of asolid adsorbent, when included in a particular formulation, illustratedby, albeit not limited to silica, and from about 25 mg to about 500 mgof a water-soluble solid excipient, illustrated by, albeit not limitedto, spray dried mannitol. In some instances the water-soluble solidexcipient, illustrated by, albeit not limited to, spray dried mannitol,may function as the only solid adsorbent and as the water-soluble solidexcipient in the particular formulation. In the case of certainformulations, an effective amount of a co-solvent may be necessary inorder to enhance the transport of the active ingredient through themucosal membrane. In such instances up to 5 mg per tablet is consideredan effective amount to facilitate such transport, illustrated by, albeitnot limited to ethanol.

In the illustrated embodiments, the tablet further contains at least onedisintegrant and one lubricant. Although the disintegrant has beenexemplified in the formulations in Table 6, 7 and 8 as sodium starchglycolate, it is nevertheless within the purview of this invention tosubstitute any functionally equivalent disintegrant, illustrated by, butnot limited to, crospovidone, croscarmellose sodium, low-substitutedhydroxypropyl cellulose, starch, microcrystalline cellulose and mixturesthereof. The content of the disintegrant is from about 0.5 mg to about50 mg.

In the illustrated embodiments, the tablet further contains at least onelubricant. Although the lubricant has been exemplified in theformulations in Table 6, 7 and 8 as sodium stearyl fumarate, it isnevertheless within the purview of this invention to substitute anyfunctionally equivalent lubricant, illustrated by, but not limited to,magnesium stearate, stearic acid, sodium lauryl sulfate, talc,polyethylene glycol, calcium stearate and mixtures thereof. The contentof the lubricant is from about 0.1 mg to about 15 mg.

Example 6

In one embodiment, the invention provides a 2 mg strength nicotinesublingual tablet having a total tablet weight of about 50 mg, whereinthe tablet comprises nicotine, a solid adsorbent, such as silica; awater-soluble solid excipient, such as mannitol; a disintegrant, such assodium starch glycolate; and a lubricant, such as sodium stearylfumarate. In such an embodiment, nicotine is mixed with oleic acid. Anexemplary formulation in accordance with the described formulation ofthis embodiment is provided in Table VI, below.

TABLE VI 2 mg Nicotine Sublingual Tablet Formulation INGREDIENT AMOUNT(mg/tablet) Nicotine 2.0 Oleic acid 3.5 Silica 4.0 Mannitol 38.5 SodiumStarch Glycolate 1.5 Sodium Stearyl Fumarate 0.5 Total Tablet Weight50.0

Example 2

In one embodiment, the invention provides a 1 mg strength nicotinesublingual tablet having a total tablet weight of about 74 mg. In thisexemplary embodiment, nicotine is mixed with oleic acid and theco-solvent ethanol. An exemplary formulation manufactured for thisembodiment in accordance with the subject invention is provided in TableVII, below.

TABLE VII 1 mg Nicotine Sublingual Tablet Formulation INGREDIENT AMOUNT(mg/tablet) Nicotine 1.0 Oleic Acid 1.7 Ethanol 0.5 Silica 2.3 Mannitol65.0 Sodium Starch Glycolate 2.0 Sodium Stearyl Fumarate 1.5 TotalTablet Weight 74.0

Example 8

In one embodiment, the invention provides a 0.5 mg strength nicotinesublingual tablet having a total tablet weight of about 102 mg. In thisexemplary embodiment, nicotine is mixed with oleic acid and added tospray dried mannitol, which functions as the water-soluble solidexcipient and solid adsorbent. An exemplary formulation manufactured forthis embodiment in accordance with the subject invention is provided inTable VIII, below.

TABLE VIII 0.5 mg Nicotine Sublingual Tablet Formulation INGREDIENTAMOUNT (mg/tablet) Nicotine 0.5 Oleic Acid 1.0 Mannitol 95.5 SodiumStarch Glycolate 3.0 Sodium Stearyl Fumarate 2.0 Total Tablet Weight102.0

Example 9

The rate of drug release from a dosage form is a prerequisite forsystemic absorption. Dissolution study comparing a 2 mg sublingualnicotine tablet prepared in accordance with Example 6 of the instantinvention to the current art represented by 2 mg sublingual nicotinetablet Microtab® marketed by McNeil, a Johnson & Johnson company. FIG. 7shows the invention released nicotine much faster than MicroTab®,resulting in about 90% release in 10 minutes compared to taking about 30minutes for Microtab®.

Although drug dissolution is a prerequisite to drug absorption it is notvery predictive of systemic absorption, pharmacokinetics orbioavailability. However, in-vitro permeation studies are much morepredictive, wherein a drug's penetration through a relevant biologicalmembrane is measured. An oral mucosa permeation study was conductedcomparing 2 mg Microtab® to a 2 mg nicotine sublingual tablet accordingto Example 6. This study used oral mucosal tissue mounted in a Franzcell and the drug concentration was measured by high pressure liquidchromatograph (HLPC) in the receiver solution over time. The tabletswere wetted with 0.5 ml water at the beginning of the test, and sampleswere taken from the receiver side of the Franz cell over time This datashows the invention has much faster permeation through the mucosaltissue compared to Microtab®, see FIG. 8. This shows that the inventionhas faster absorption, higher bioavailability and a faster onset ofaction compared to Microtab®.

Based on publically available information and actual human plasmanicotine data from the administration of two 2 mg sublingual tabletsmanufactured as per Example 6 of the invention, a graph has beenprepared comparing the invention to representative nicotine plasmaconcentrations obtained from two currently marketed nicotine replacementtherapies (NRTs), and cigarettes, see FIG. 9. Note that the time tomaximum plasma concentration (Tmax) occurs between 5 and 15 minutes forcigarettes and the invention, compared to about 60 minutes forNicorette® gum and Microtab® sublingual tablet. This clearlydemonstrates that the instant invention increases oral absorption andbioavailability, while shortening the onset of nicotine action. Thisgraph also shows that the invention mimics the nicotine plasma profileobtained from smoking a cigarette and should therefore satisfy asmoker's nicotine cravings.

FIG. 10 shows human plasma nicotine data and vital signs obtained fromthe administration of two tablets prepared according to the Example 6.This data shows that the time to maximum nicotine plasma concentration(Tmax) occurred in about 7 minutes. The vital sign data shows that thepulse and systolic/diastolic blood pressure peak in less than 5 minutesafter administration. Thus, the physiological effects of nicotine arefelt within a few minutes, just like a cigarette.

The steps of dissolving the active ingredient, e.g. nicotine, to form anactive ingredient-containing solution followed by contacting of theactive ingredient-containing solution with the solid absorbent/adsorbentcarrier whereby said active ingredient-containing solution is coated,absorbed or adsorbed onto said carrier are unique to the instantinvention, and the carrying out of said steps are what allow for theformation of a unique solid dosage form which enables increased oralabsorption and bioavailability while shortening onset of activeingredient action upon administration of the novel solid dosage form viathe buccal or sublingual route.

Example 5

A method of manufacture for a tablet according to an embodiment of thesubject invention for sublingual/buccal administration may employ anysuitable method known in the art including, but not limited to, theaddition of the nicotine and oleic acid mixture with or without aco-solvent to pre-manufactured tablets, cold compressions with inertfillers and binders, direct tablet compression blends, direct powderblends, wet or dry granulations, molding, lyophilization,microencapsulation, freeze drying, spray-congealing, spray-drying,co-melt, spheronization, triturates, troching, powder layering,pelleting, encapsulation.

An exemplary method for the manufacture of a direct compression tabletof the formulation given in Example 6 is outlined below and isschematically diagramed in FIG. 1:

Embodiment 1 Manufacturing

STEP 1: Mix nicotine and oleic acid together. STEP 2: Blend the nicotineand oleic acid mixture from Step 1 with silica until homogeneous to forma silica blend. STEP 3: Add to the silica blend from Step 2, mannitoland sodium starch glycolate and mix until homogeneous to form a furtherblend. STEP 4: Add sodium stearyl fumarate to the further blend fromStep 3 and blend until well lubricated to form a lubricated blend. STEP5: Compressing the lubricated blend from Step 4 into 50 mg tablets using7/16 inch round tooling.

Method of packaging. The sublingual/buccal tablets may be packaged insuch a manner as to aid in maintaining stability. Packaging methods andmaterials may include, but are not limited to, blister packaging in afoil/foil, foil/Acrylonitrile, foil/Polychlorotrifluoroethylenelaminates for blister packaging or glass and plastic bottles.

Method of Use: In an embodiment, nicotine sublingual tablet formulationaccording to the invention is useful in the treatment of tobaccodependence and other conditions and disease states for which nicotine isan effective therapeutic. The typically treatment regimen starts byplacing the nicotine tablet under the tongue and leaving it undisturbedfor about 5 to 15 minutes.

All references cited herein are incorporated herein by reference. Wherethe meaning of any term as used within the application itself differsfrom the meaning of that same term in any of the references, the meaningof the term as used within the application itself controls.

It is to be understood that the embodiments described above are intendedto be illustrative and not restrictive. Many other embodiments will beapparent to those of skill in the art once they have read the abovedescription. The foregoing description and embodiments are thereforemerely exemplary and are not intended to limit the scope of theinvention, which encompasses all equivalents of what is described hereinand set forth particularly by the appended claims.

REFERENCES

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1. A pharmaceutical composition in a solid dosage form for buccal orsublingual delivery, comprising: ketamine; a fatty acid in which theketamine is solvated; and a solid adsorbent to which solvated ketamineis adsorbed, the adsorbent being a silica or silicified microcrystallinecellulose, wherein the ketamine in the solid dosage form of thecomposition is in solution.
 2. The pharmaceutical composition of claim1, wherein the fatty acid is caproic acid, oleic acid, caprylic acid,lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid,gadoleic acid, erucic acid, ricinoleic acid, linoleic acid, linoleicacid, licanic acid, arachidonic acid, clupanodonic acid, or mixturesthereof.
 3. The pharmaceutical composition of claim 2, wherein the fattyacid comprises oleic acid.
 4. The pharmaceutical composition of claim 1,further including a co-solvent.
 5. The pharmaceutical composition ofclaim 4, wherein the co-solvent comprises polyethylene glycol (PEG),ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,tributyl citrate, substituted polyethylene glycols, bisabolol, glycerin,mineral oil, ethyl oleate, squalane, animal oils, vegetable oils,propylene glycol, hydrogenated vegetable oils, isopropyl myristate,isopropyl palmitate, glycofurol, terpenes, essential oils, alcohols,polyols, silicone fluids, or mixtures thereof.
 6. The pharmaceuticalcomposition of claim 5, wherein the co-solvent comprises ethanol.
 7. Thepharmaceutical composition of claim 1, further comprising a solid,water-soluble excipient, a disintegrant, a lubricant, or mixturesthereof.
 8. The pharmaceutical composition of claim 7, furthercomprising a co-solvent.
 9. The pharmaceutical composition of claim 7,wherein the solid water-soluble excipient is selected from the groupconsisting of a sugar, a polyol, a saccharide, a polysaccharide, adextrate, a dextrin, dextrose, fructose, lactitol, lactose, erythritol,maltose, maltitol, a maltodextrin, a polydextrose, trehalose, mannitol,a polyethylene glycol, sorbitol, sucrose, xylitol and mixtures thereof.10. The pharmaceutical composition of claim 9, wherein the water-solubleexcipient, comprises mannitol.
 11. The pharmaceutical composition ofclaim 9, wherein the disintegrant is selected from the group consistingof sodium starch glycolate, crospovidone, croscarmellose sodium,low-substituted hydroxypropyl cellulose, starch, microcrystallinecellulose and mixtures thereof.
 12. The pharmaceutical composition ofclaim 11, wherein the disintegrant comprises low-substitutedhydroxypropyl cellulose.
 13. The pharmaceutical composition of claim 7,wherein the lubricant is selected from the group consisting of sodiumstearyl fumarate, magnesium stearate, stearic acid, sodium laurylsulfate, talc, polyethylene glycol, calcium stearate and mixturesthereof.
 14. The pharmaceutical composition of claim 13, wherein thelubricant comprises sodium stearyl fumarate.
 15. The pharmaceuticalcomposition of claim 1, comprising: about 0.1 mg to about 20 mg ketamineabout 0.4 mg to about 80 mg fatty acid; and up to about 200 mgadsorbent.
 16. The pharmaceutical composition of claim 15, furthercomprising a co-solvent in an amount up to about 50 mg.
 17. Thepharmaceutical composition of claim 15, further comprising: about 25 mgto about 500 mg solid water-soluble excipient; about 0.5 mg to about 150mg disintegrant; and/or about 0.1 mg to about 20 mg lubricant.
 18. Thepharmaceutical composition of claim 1, which is in the form of a tablet.19. A process for the preparation of the pharmaceutical composition ofclaim 1, comprising: solvating ketamine in the pharmaceuticallyacceptable fatty acid to form a solvated drug solution; and adsorbingthe solvated drug solution to the adsorbent, the solvated drug solutionbeing in liquid form in the adsorbent.
 20. A process for the preparationof the pharmaceutical composition of claim 7, comprising: solvatingketamine in the pharmaceutically acceptable fatty acid and co-solvent toform a solvated drug solution; adsorbing the solvated drug solution tothe adsorbent; mixing the solvated drug solution/adsorbent with awater-soluble excipient, a disintegrant, and/or a lubricant; andcompressing the solvated drug solution, adsorbent, disintegrant,excipient, and/or lubricant into the tablet form, the solvated drugsolution being in liquid form in the adsorbent.
 21. A method fortreating depression, suicidal ideation, pain, anesthesia, analgesia posttraumatic shock disorder, and other central nervous systems diseasestates for which ketamine is an effective therapeutic, in a patient inneed thereof, comprising: administering the pharmaceutical compositionof claim 1 to the buccal or sublingual cavity of the patient, whereby atherapeutically effective amount of ketamine is released and issystemically administered to the patient within 5 minutes to 15 minutes.22. A method for treating depression, suicidal ideation, pain,anesthesia, analgesia post traumatic shock disorder, and other centralnervous systems disease states for which ketamine is an effectivetherapeutic, in a patient in need thereof, comprising: administering thepharmaceutical composition of claim 7 to the buccal or sublingual cavityof the patient, whereby a therapeutically effective amount of ketamineis released and is systemically administered to the patient within 5minutes to 15 minutes.
 23. The pharmaceutical composition of claim 1,wherein ketamine is an R enantiomer, an S enantiomer, or a mixturethereof.
 24. The pharmaceutical composition of claim 7, wherein ketamineis an R enantiomer, an S enantiomer, or a mixture thereof.
 25. A methodfor treating depression, suicidal ideation, pain, anesthesia, analgesiapost traumatic shock disorder, and other central nervous systems diseasestates for which ketamine is an effective therapeutic, in a patient inneed thereof, comprising: administering the pharmaceutical compositionof claim 23 to the buccal or sublingual cavity of the patient, whereby atherapeutically effective amount of ketamine is released and issystemically administered to the patient within 5 minutes to 15 minutes.26. A method for treating depression, suicidal ideation, pain,anesthesia, analgesia post traumatic shock disorder, and other centralnervous systems disease states for which ketamine is an effectivetherapeutic, in a patient in need thereof, comprising: administering thepharmaceutical composition of claim 24 to the buccal or sublingualcavity of the patient, whereby a therapeutically effective amount ofketamine is released and is systemically administered to the patientwithin 5 minutes to 15 minutes.